Reflex control of sympathetic outflow and depressed baroreflex sensitivity following myocardial infarction

Reflex control of heart rate is frequently impaired following myocardial infarction. This is referred to as depressed baroreflex sensitivity. The aim of these experiments was to assess the function of other autonomic reflexes in dogs with depressed baroreflex sensitivity. Comparisons were made to dogs in whom baroreflex sensitivity was preserved or unchanged after myocardial infarction. Under chloralose-barbiturate anesthesia, reflex control of sympathetic outflow by the sinoaortic baroreceptors was determined by measurement of changes in systolic arterial pressure and efferent renal sympathetic nerve activity during infusion of phenylephrine. Following sinoaortic denervation, reflex control of sympathetic outflow by cardiac receptors with vagal afferent fibers was determined by measurement of changes in pulmonary capillary wedge pressure and renal nerve activity during blood volume expansion. Reflex decreases in renal nerve activity in response to increases in arterial pressure were similar in the two groups of dogs. In contrast, elevation of pulmonary capillary wedge pressure elicited significantly greater reflex decreases in renal nerve activity in dogs with depressed baroreflex sensitivity following myocardial infarction compared to dogs with preserved baroreflex sensitivity. Hemodynamic parameters and infarct sizes were similar in each group. In conclusion, activation of cardiac receptors with vagal afferent fibers elicited greater reflex inhibition of sympathetic outflow in dogs with depressed baroreflex sensitivity following myocardial infarction. These data suggest that these receptors are "sensitized". These results provide additional support for the hypothesis that depressed reflex control of heart rate following myocardial infarction is related to augmented afferent input from the left ventricle.     

Comparison of voluntary and reflex cough effectiveness in Parkinson's disease

IntroductionMultiple airway protective mechanisms are impacted with Parkinson's disease (PD), including swallowing and cough. Cough serves to eject material from the lower airways, and can be produced voluntarily (on command) and reflexively in response to aspirate material or other airway irritants. Voluntary cough effectiveness is reduced in PD however it is not known whether reflex cough is affected as well. The goal of this study was to compare the effectiveness between voluntary and reflex cough in patients with idiopathic PD.MethodsTwenty patients with idiopathic PD participated. Cough airflow data were recorded via facemask in line with a pneumotachograph. A side delivery port connected the nebulizer for delivery of capsaicin, which was used to induce cough. Three voluntary coughs and three reflex coughs were analyzed from each participant. A two-way repeated measures analysis of variance was used to compare voluntary versus reflex cough airflow parameters.ResultsSignificant differences were found for peak expiratory flow rate (PEFR) and cough expired volume (CEV) between voluntary and reflex cough. Specifically, both PEFR and CEV were reduced for reflex as compared to voluntary cough.ConclusionCough PEFR and CEV are indicative of cough effectiveness in terms of the ability to remove material from the lower airways. Differences between these two cough types likely reflect differences in the coordination of the respiratory and laryngeal subsystems. Clinicians should be aware that evaluation of cough function using voluntary cough tasks overestimates the PEFR and CEV that would be achieved during reflex cough in patients with PD.     

Reciprocal and non-reciprocal action of the vagal and sympathetic nerves innervating the heart

Simultaneous recordings were made from vagal and sympathetic fibers innervating the heart in dogs anesthetized with chloralose. Reciprocal relationship between the two autonomic nerves was clearly seen in the baroreceptor reflex. Stimulation of chemoreceptors, however, evoked non-reciprocal responses of the two nerves; at the onset of the chemoreceptor reflex cardiac vagal and sympathetic discharges both increased, then, as baroreceptors became excited due to a pressor response, sympathetic nerve activity suddenly decreased while vagal discharges remained high, indicating the appearance of the reciprocal action typifying the baroreceptor reflex. Decrease in ventilatory volume and a slight increase in end-expired CO2 level augmented greatly both vagal and sympathetic discharges. As the phrenic-locked activity of the two nerves (i.e. the activity in vagus nerve occurs only in the absence of phrenic bursts while sympathetic discharges increase with phrenic bursts) increased, the alternate discharges between the two nerves became more conspicuous and the heart rate fluctuated with the respiratory (phrenic) rhythm. Thus, strong reciprocity between vagus and sympathetic can result in an oscillatory heart rate. When ventilatory volume was increased, both nerve activities decreased below control level. Mild hypoxia had similar effects to hypercapnia though changes in nerve activity were greater. When coactivation of vagal and sympathetic nerve was produced in reflex action, changes in vagal discharges occurred earlier and faster than in the sympathetic fibers. The magnitude of change in vagus activity was also far greater. The elimination of afferents in the vagi, the aortic and sinus nerves reduced cardiac vagal activity greatly. However, discharges were still present and occurred between phrenic bursts, indicating that the vagal "tone" is maintained centrally as well as peripherally by input from receptors in the cardiovascular system. The physiological significance of reciprocal and non-reciprocal control of vagal and sympathetic nerves innervating the heart was discussed.     

Cough-related neural processing in the brain: A roadmap for cough dysfunction?

Cough is a complex respiratory behavior essential for airway protection, consisting of sensory, motor, affective and cognitive attributes. Accordingly, the cough neural circuitry extends beyond a simple pontomedullary reflex arc to incorporate a network of neurons that are also widely distributed throughout the subcortical and cortical brain. Studies have described discrete regional responses in the brain that likely give rise to sensory discriminative processes, voluntary and urge-related cough control mechanisms and aspects of the emotive responses following airways irritation and coughing. Data from these studies highlight the central nervous system as a plausible target for therapeutic intervention and, consistent with this, a careful appraisal of the many and varied clinical disorders of coughing control would argue that more diversified therapies are needed to treat patients with cough dysfunction. In this paper we explore these concepts in detail to highlight unanswered questions and stimulate discussion for potential research of cough in the future.     

The excitatory amino acid glutamate mediates reflexly increased tracheal blood flow and airway submucosal gland secretion

In six decerebrated and in eight alpha-chloralose anesthetized, paralyzed and mechanically ventilated beagle dogs, we have studied involvement of glutamate and glutamate receptors in transmission of excitatory inputs from the airway sensory receptors to the nucleus tractus solitarius and from this site to airway-related vagal preganglionic cells that regulate the tracheal circulation and the submucosal gland secretion. Stimulation of airway sensory fibers by lung deflation-induced reflex increase in tracheal blood flow and submucosal gland secretion. These responses were diminished by prior administration of AMPA/kainate receptor antagonist CNQX into the fourth ventricle (n=6). Furthermore, topical application or microinjection of AMPA/kainate receptor blockers, into the region of the ventrolateral medulla, where airway-related vagal preganglionic neurons are located, abolished the reflex changes in tracheal submucosal gland secretion (n=8); in these dogs mucosal blood flow was not measured). These findings indicate that reflex increase in tracheal blood flow and submucosal gland secretions are mediated mainly via release of glutamate and activation of the AMPA/kainate subtype of glutamate receptors.     

Parasympathetic control of airway submucosal glands: central reflexes and the airway intrinsic nervous system

Airway submucosal glands produce the mucus that lines the upper airways to protect them against insults. This review summarizes evidence for two forms of gland secretion, and hypothesizes that each is mediated by different but partially overlapping neural pathways. Airway innate defense comprises low level gland secretion, mucociliary clearance and surveillance by airway-resident phagocytes to keep the airways sterile in spite of nearly continuous inhalation of low levels of pathogens. Gland secretion serving innate defense is hypothesized to be under the control of intrinsic (peripheral) airway neurons and local reflexes, and these may depend disproportionately on non-cholinergic mechanisms, with most secretion being produced by VIP and tachykinins. In the genetic disease cystic fibrosis, airway glands no longer secrete in response to VIP alone and fail to show the synergy between VIP, tachykinins and ACh that is observed in normal glands. The consequent crippling of the submucosal gland contribution to innate defense may be one reason that cystic fibrosis airways are infected by mucus-resident bacteria and fungi that are routinely cleared from normal airways. By contrast, the acute (emergency) airway defense reflex is centrally mediated by vagal pathways, is primarily cholinergic, and stimulates copious volumes of gland mucus in response to acute, intense challenges to the airways, such as those produced by very vigorous exercise or aspiration of foreign material. In cystic fibrosis, the acute airway defense reflex can still stimulate the glands to secrete large amounts of mucus, although its properties are altered. Importantly, treatments that recruit components of the acute reflex, such as inhalation of hypertonic saline, are beneficial in treating cystic fibrosis airway disease. The situation for recipients of lung transplants is the reverse; transplanted airways retain the airway intrinsic nervous system but lose centrally mediated reflexes. The consequences of this for gland secretion and airway defense are poorly understood, but it is possible that interventions to modify submucosal gland secretion in transplanted lungs might have therapeutic consequences.     

Ventricular reflex interactions during transmural myocardial ischemia

The role of left ventricular receptors with sympathetic afferent fibers in the reflex response to myocardial ischemia is controversial, particularly in the canine model. Previous experiments have shown that reflex excitatory responses mediated by left ventricular sympathetic afferents can be detected in sinoaortic denervated and vagotomized dogs during transmural myocardial ischemia. The purpose of these experiments was to determine if reflex excitatory responses occur in dogs with intact left ventricular vagal afferents. Experiments were performed in 27 chloralose-anesthetized dogs with sinoaortic denervation. Responses of efferent renal sympathetic nerve activity, arterial, and left atrial pressures to transmural and non-transmural inferoposterior myocardial ischemia were measured before and after interruption of left ventricular sympathetic afferents by stellectomy. The adequacy of sympathetic deafferentation was assessed by measurement of renal nerve responses to epicardial bradykinin. Prior to stellectomy, excitatory responses were observed in 10 animals and inhibitory responses in 9 animals. The remaining animals had no responses and were excluded from analysis. In the excitatory group, reflex increases in renal nerve activity during both transmural and non-transmural inferoposterior ischemia were abolished by stellectomy and not replaced by inhibitory responses. In the inhibitory group, non-transmural inferoposterior ischemia elicited greater reflex decreases in renal nerve activity when left ventricular sympathetic afferents were intact. After stellectomy, transmural ischemia elicited greater reflex inhibition of renal nerve activity. Renal nerve responses to epicardial bradykinin were abolished by stellectomy. These results indicate that reflex excitatory responses mediated by left ventricular receptors with sympathetic afferent fibers can be elicited in dogs with intact vagal afferents. These excitatory responses are most apparent during transmural myocardial ischemia. In dogs with inhibitory responses to coronary occlusion, activation of sympathetic afferents during transmural ischemia appears to attenuate reflex inhibitory responses mediated by left ventricular vagal afferents.     

Changes of gastric emptying rate and gastrin levels are early indicators of autonomic neuropathy in type II diabetic patients

The authors investigated the effect of a balanced meal on gastric emptying rate and gastrin plasma concentrations in patients with type II diabetes and autonomic neuropathy, in diabetic patients without autonomic neuropathy, and in healthy subjects (controls). Before food the gastrin plasma concentrations were higher in patients with diabetes with autonomic neuropathy. After food, gastric emptying rate was slower in patients with diabetes with autonomic neuropathy, whereas gastrin plasma concentrations increased in 30 minutes in all groups but to a greater extent in patients with diabetes with autonomic neuropathy. Sixty minutes after food, there was a significant decrease in gastrin plasma concentrations in patients with diabetes with autonomic neuropathy, compared with the other two groups. These data suggest that in patients with type II diabetes with autonomic neuropathy, food causes slower gastric emptying and different plasma gastrin level responses from those in patients with type II diabetes without autonomic neuropathy and controls. There are therefore differences in the responses to food ingestion between these groups because of vagal denervation induced by autonomic neuropathy. These tests should be reserved for patients with symptoms suggestive of disturbed gastric emptying, or for patients with autonomic neuropathy without symptoms of gastroparesis.     

Descending Modulation of Laryngeal Vagal Sensory Processing in the Brainstem Orchestrated by the Submedius Thalamic Nucleus

The nodose and jugular vagal ganglia supply sensory innervation to the airways and lungs. Jugular vagal airway sensory neurons wire into a brainstem circuit with ascending projections into the submedius thalamic nucleus (SubM) and ventrolateral orbital cortex (VLO), regions known to regulate the endogenous analgesia system. Here we investigate whether the SubM–VLO circuit exerts descending regulation over airway vagal reflexes in male and female rats using a range of neuroanatomical tracing, reflex physiology, and chemogenetic techniques. Anterograde and retrograde neuroanatomical tracing confirmed the connectivity of the SubM and VLO. Laryngeal stimulation in anesthetized rats reduced respiration, a reflex that was potently inhibited by activation of SubM. Conversely, inhibition of SubM potentiated laryngeal reflex responses, while prior lesions of VLO abolished the effects of SubM stimulation. In conscious rats, selective chemogenetic activation of SubM neurons specifically projecting to VLO significantly inhibited respiratory responses evoked by inhalation of the nociceptor stimulant capsaicin. Jugular vagal inputs to SubM via the medullary paratrigeminal nucleus were confirmed using anterograde transsynaptic conditional herpes viral tracing. Respiratory responses evoked by microinjections of capsaicin into the paratrigeminal nucleus were significantly attenuated by SubM stimulation, whereas those evoked via the nucleus of the solitary tract were unaltered. These data suggest that jugular vagal sensory pathways input to a nociceptive thalamocortical circuit capable of regulating jugular sensory processing in the medulla. This circuit organization suggests an intersection between vagal sensory pathways and the endogenous analgesia system, potentially important for understanding vagal sensory processing in health and mechanisms of hypersensitivity in disease.SIGNIFICANCE STATEMENT Jugular vagal sensory pathways are increasingly recognized for their important role in defensive respiratory responses evoked from the airways. Jugular ganglia neurons wire into a central circuit that is notable for overlapping with somatosensory processing networks in the brain rather than the viscerosensory circuits in receipt of inputs from the nodose vagal ganglia. Here we demonstrate a novel and functionally relevant example of intersection between vagal and somatosensory processing in the brain. The findings of the study offer new insights into interactions between vagal and spinal sensory processing, including the medullary targets of the endogenous analgesia system, and offer new insights into the central processes involved in airway defense in health and disease.     

Is there a relationship between somatic and autonomic neuropathies in chronic alcoholics?

We investigated the relationship between somatic and autonomic neuropathy in 40 chronic alcoholics. Electromyographic and neurographic studies of upper and lower limbs and a battery of six cardiovascular reflex tests were carried out. A score for somatic or autonomic neuropathy was calculated. All parameters were investigated for possible relationship with total life dose (TLD) of alcohol intake. Somatic neuropathy was detected in 25 patients (62.5%) and autonomic neuropathy in 13 patients (32.5%). Nineteen patients (47.5%) presented only a somatic neuropathy, six patients (15%) had only an autonomic neuropathy, and seven (17.5%) had a combined somatic and autonomic neuropathy. TLD was significantly higher in the group of patients with combined neuropathy than in the group with isolated somatic neuropathy. There was no significant correlation between laboratory parameters of somatic and autonomic neuropathy. Our findings do not support the existence of a parallel involvement of peripheral somatic and autonomic cardiovascular nerve fibers in chronic alcoholism.     

Efferent discharges of sympathetic and parasympathetic nerve fibers during increased intracranial pressure in anesthetized cats in the absence and presence of pressor response

Efferent discharges of the cervical sympathetic cardiovascular and vagal type 1 fibers in response to increased intracranial pressure (ICP) were simultaneously recorded in cats anesthetized with pentobarbitone and ventilated artificially. Sympathetic outflow of renal nerve fibers was also recorded in some animals. The type 1 fibers were assumed to be cardiac vagal fibers, from the response behavior such a pulse-synchronicity to respiratory and heart rhythm, reflex activation from arterial baroreceptors and reciprocal relationship of the activity to sympathetic ones during slower fluctuations of hemodynamic changes, and which occur spontaneously during Mayer waves. The vagal type 1 discharges increased to various amplitudes with increase in ICP and in the absence and the presence of pressor response. Efferent outflow of the renal and cervical sympathetic fibers frequently decreased with a moderate increase in ICP. There was a slight decrease or no apparent change in the blood pressure, and a higher elevation of ICP ensued. Heart rates decreased with increase in ICP, while the rate frequently increased with levels of ICP over about 120 mm Hg. Changes in the vagal and sympathetic discharges always began at a time before the initiation of cardiovascular response to the elevated ICP. However, when ICP was repeatedly increased, the increase in vagal discharges progressively decayed and was accompanied by vigorous sympathetic firings and a marked pressor response. The sympathetic outflow also decayed following the decrease in vagal activities. The present findings of changes in the vagal type 1 discharges demonstrate clear participation of parasympathetic as well as sympathetic nerve activity in the occurrence of cardiovascular responses to increased ICP. Changes in both these autonomic nerve responses may explain the initial fall in arterial blood pressure and pressor responses associated with bradycardia or tachycardia, at different levels of elevated ICP.     

Functional and chemical anatomy of the afferent vagal system

The results of neural tracing studies suggest that vagal afferent fibers in cervical and thoracic branches innervate the esophagus, lower airways, heart, aorta, and possibly the thymus, and via abdominal branches the entire gastrointestinal tract, liver, portal vein, billiary system, pancreas, but not the spleen. In addition, vagal afferents innervate numerous thoracic and abdominal paraganglia associated with the vagus nerves. Specific terminal structures such as flower basket terminals, intraganglionic laminar endings and intramuscular arrays have been identified in the various organs and organ compartments, suggesting functional specializations. Electrophysiological recording studies have identified mechano- and chemo-receptors, as well as temperature- and osmo-sensors. In the rat and several other species, mostly polymodal units, while in the cat more specialized units have been reported. Few details of the peripheral transduction cascades and the transmitters for signal propagation in the CNS are known. Glutamate and its various receptors are likely to play an important role at the level of primary afferent signaling to the solitary nucleus. The vagal afferent system is thus in an excellent position to detect immune-related events in the periphery and generate appropriate autonomic, endocrine, and behavioral responses via central reflex pathways. There is also good evidence for a role of vagal afferents in nociception, as manifested by affective-emotional responses such as increased blood pressure and tachycardia, typically associated with the perception of pain, and mediated via central reflex pathways involving the amygdala and other parts of the limbic system. The massive central projections are likely to be responsible for the antiepileptic properties of afferent vagal stimulation in humans. Furthermore, these functions are in line with a general defensive character ascribed to the vagal afferent, paraventricular system in lower vertebrates.     

Minocycline improves peripheral and autonomic neuropathy in type 2 diabetes: MIND study

Diabetic peripheral neuropathy and diabetic autonomic neuropathy are serious and common complications of diabetes associated with increased risk of mortality and cardiovascular disease. We sought to evaluate the safety and efficacy of minocycline in type 2 diabetic patients with diabetic peripheral and autonomic neuropathy. In a randomized placebo controlled study, 50 outpatients were randomly assigned to receive 100 mg minocycline or placebo. Outcome measures included the vibration perception threshold (VPT), Leeds assessment of neuropathic symptoms and signs (LANSS), Pain Disability Index (PDI), Visual Analog Scale (VAS), beck depression inventory (BDI), health assessment questionnaire (HAQ) and autonomic neuropathy, assessed by cardiovascular reflex tests according to Ewing and peripheral sympathetic autonomic function was assessed by FDA approved Sudoscan. At baseline there were no significant differences between demographic variables and the neuropathy variables in the minocycline and placebo groups. After treatment, VPT significantly improved in the minocycline group as compared to the placebo group. Mean posttreatment scores on the LANSS, PDI and HAQ were significantly lower in the minocycline group compared with the placebo group. However, BDI and VAS significantly (p = 0.01) improved in both minocycline and placebo groups (Table 2). After treatment with minocycline, heart rate (HR) response to standing significantly improved, while there was a borderline significance toward a reduction in HR response to deep breath. These finding indicate that 6-week oral treatment with minocycline is safe, well tolerated and significantly improves peripheral and autonomic neuropathy in type 2 diabetic patients.     

Tachyphylaxis to capsaicin-induced cough and its reversal by indomethacin,in patients with the sinobronchial syndrome

Cough reflex testing with capsaicin has been used to study the pathophysiology of the cough reflex and the antitussive effects of various drugs. Although the reproducibility of capsaicin-induced cough has been well established in normal subjects, it is not known if prior challenge with capsaicin reduces the subsequent cough response to inhaled capsaicin in patients with the sinobronchial syndrome, a condition characterized by chronic upper and lower airway inflammation. Measurement of the capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was repeated four times at intervals of 15, 30 and 60 min in eleven patients with the SBS and ten normal subjects. The cough thresholds at 15, 30 and 60 min were greater than the initial value in patients with the SBS but not in normal subjects. In addition, we examined the effect of 4 days treatment with indomethacin (100 mg/day) on the cough thresholds measured twice at an interval of 15 min in eight patients with the SBS. Indomehacin increased the initial cough threshold and reduced the increment in the post-15 min cough threshold from the initial value compared with placebo, thus reducing the tachyphylaxis. These results indicate that chronic airway inflammation may be responsible for the decreased response (tachyphylaxis) to repeated inhalation of capsaicin, and suggest that cyclooxygenase products released by the airway inflammation may be involved in tachyphylaxis, cough receptor sensitivity to inhaled capsaicin, or both, in patients with the SBS.     

Disorders of the autonomic nervous system: Part 1. Pathophysiology and clinical features

Autonomic dysfunction may result from diseases that affect primarily either the central nervous system or the peripheral autonomic nervous system. The most common pathogenesis of disturbed autonomic function in central nervous system diseases is degeneration of the intermediolateral cell columns (progressive autonomic failure) or disease or damage to descending pathways that synapse on the intermediolateral column cells (spinal cord lesions, cerebrovascular disease, brainstem tumors, multiple sclerosis). The peripheral autonomic nervous system may be damaged in isolation in the acute and subacute autonomic neuropathies or in association with a generalized peripheral neuropathy. The peripheral neuropathies most likely to cause severe autonomic disturbance are those in which small myelinated and unmyelinated fibers are damaged in the baroreflex afferents, the vagal efferents to the heart, and the sympathetic efferent pathways to the mesenteric vascular bed. Acute demyelination of the sympathetic and parasympathetic nerves in the Guillain-Barré syndrome may also cause acute autonomic dysfunction. Although autonomic disturbances may occur in other types of peripheral neuropathy, they are rarely clinically important.     

Autonomic nerve and cardiovascular responses to changing blood oxygen and carbon dioxide levels in the rat

Contribution of autonomic nervous system activity to the heart rate and blood pressure responses during chemoreceptor excitations by systemic hypoxia and hypercapnia and to hyperoxia and hypocapnia was analyzed in the urethane-anesthetized, artificially ventilated rats. Systemic hypoxia induced a co-activation of two antagonistic nerves: an increase in cardiac sympathetic and in cardiac vagal efferent nerve discharges. Increased heart rate was due to predominance of the cardiac sympathetic over the cardiac vagal activation. In spite of a marked reflex increase in the renal and cardiac sympathetic nerve activities, the local vasodilator effect of hypoxia prevented consistent changes in arterial blood pressure. Bilateral section of the carotid sinus nerves (CSN) mostly abolished autonomic nerve responses and produced a profound decreases in the blood pressure during hypoxia. Hyperoxia elicited a pressor response due to peripheral vasoconstriction with no significant change in the autonomic nerve activities except for a decrease in the cardiac sympathetic nerve discharges. Hypercapnia significantly increased blood pressure and renal nerve sympathetic activity. In contrast to hypoxia, hypercapnia excited cardiac sympathetic and inhibited cardiac vagal activity. This reciprocal effect did not elicit neurogenic cardioacceleration, because it was masked by the local inhibitory action of CO2 on the heart rate. The increase in sympathetic activities and in blood pressure during hypercapnia persisted after bilateral CSN section indicating that the responses were mediated by central rather than by peripheral chemoreceptors. Hypocapnia produced a significant increase in cardiac vagal discharges yet a cardioacceleratory response occurred due to the local effect upon heart rate. The present results indicate that in the rat, autonomic nervous responses differ depending on the type, i.e. hypoxic or hypercapnic, chemoreceptor stimuli. Reflex heart rate and blood pressure responses do not follow the autonomic nerve activities exactly. Circulatory responses are greatly modified by local peripheral effects of hypoxic, hyperoxic, hypocapnic or CO2 stimuli on the cardiovascular system. Species differences characterizing the autonomic nerve responsiveness to chemical stimuli in the rat are described.     

Autonomic dysfunction in experimental allergic neuritis

Beat-to-beat variation (R-R variation) in the electrocardiogram was studied in experimental allergic neuritis in the Sprague-Dawley rat. Reduced R-R variations were found in 2 of 10 animals, probably as a sign of autonomic dysfunction. The vagal nerves from these two animals, studied in vitro, showed disturbed conduction. In one animal prolonged conduction latencies to supramaximal electrical stimuli were found. Vagal nerves from controls and from animals without clinical symptoms showed normal conduction. Histologically, the vagal nerves from affected animals showed a slight inflammatory cell infiltration and signs of demyelination but there was no evidence of involvement of the brainstem vasomotor nuclei. Thus, we suggest that the autonomic dysfunction in experimental allergic neuritis, measured as reduced R-R variations, is caused by a peripheral vagal neuropathy.     

Role of cholinergic neural transmission on airway resistance in the dog

The unique contractile profiles of bronchial smooth muscle (Kondo et al., 1995) and its neural control were investigated by comparing responses of the bronchus and trachea to acute hypercapnia, stimulation of vagus efferent fibers before and after intravenous atropine, and intravenous acetylcholine in decerebrated and paralyzed dogs. During acute hypercapnia, airway resistance represented by peak airway pressure (Pedley et al., 1970) significantly increased as well as tracheal tension (Ttr). During electric stimulation of the vagal efferent fibers, Ttr increased and was sustained throughout the simulation period while the peak airway pressure was not maintained at the peak level. The peak Ttr and the airway resistance (Raw) calculated from ventilatory flow and airway pressure increased with increases in intensity of electric stimulation. Ttr reached its maximal level at an intensity 16 times of the threshold (T), while Raw became maximal at 4T. Although both the Ttr-stimulus intensity and Raw-intensity curves were shifted to the right by administration of intravenous atropine, the Raw curve shifted more to the right than the Ttr curve with the same dose of atropine. When muscular muscarinic receptors were directly stimulated by intravenous acetylcholine, Ttr once increased and then decreased promptly while peak airway pressure remained at a high level for a few minutes. These findings suggested that the bronchus is more sensitive to vagal efferent stimulation and susceptible to competitive antagonist of actylcholine than the trachea. In conclusion, the contractile profiles of the fifth-order bronchus we have reported (Kondo et al., 1995) were reflected in airway resistance, and the neuromuscular junction may be the site of adaptation of bronchoconstrictor response to motor nerve adaptation.     

Enteropancreatic reflexes mediating the pancreatic enzyme response to nutrients

The observation that in dogs electrical stimulation of the vagus nerve elicited a strong secretory activity of the pancreas, prompted I. P. Pavlov in 1888 to conclude that the pancreatic secretory response to nutrients is mediated by enteropancreatic reflexes involving the vagus nerves. It took, however, more than 90 years until by studying the latency of pancreatic amylase response to exogenous and endogenous stimuli for the first time experimental evidence was provided for the actual existence of cholinergic vago-vagal enteropancreatic reflexes. Follow-up studies, based on stepwise extrinsic denervation of the pancreas, ruled out possible splanchnic pathways for enteropancreatic reflexes. In more recent years, experiments utilizing specific antagonists demonstrated a physiological role for both cholinergic M1 and cholecystokinin (CCK) receptors within the enteropancreatic reflex. At least a significant portion of the cholinergic fibres of the enteropancreatic reflex end on muscarinic receptors of the subtype M1. CCK, the most important hormone stimulating pancreatic enzyme secretion, appears to act at least in part on CCK receptors located on vagal afferent nerves, which in turn elicit a vago-vagal reflex, implying that CCK exerts its effect on the pancreas at least in part through vago-vagal reflexes. Furthermore, pharmacological blockade of CCK receptors totally abolished the early pancreatic amylase response to intestinal nutrients, suggesting that the activation of (probably vagal) CCK receptors is essential to run the enteropancreatic reflex.     

An hereditary sensory and autonomic neuropathy transmitted as an X-linked recessive trait.

Five members of a single family presented with neuropathic deformities and ulceration of the feet developing in the first and second decades of life, and progressed slowly over many years. In this form of hereditary sensory and autonomic neuropathy, there was minimal tendon reflex impairment, cutaneous sensory impairment was restricted to the feet, and there was no autonomic dysfunction. The only neurophysiological abnormality was that of reduced or absent sural nerve sensory action potentials. Sural nerve biopsies taken from two affected family members showed changes of a chronic neuropathy with loss of myelinated fibres, particularly affecting those of small diameter. Unmyelinated fibres were present in normal numbers. This condition differed from other forms of hereditary sensory and autonomic neuropathy having an X-linked recessive mode of inheritance.